The therapeutic community: Toward a model for implementing patients' rights in psychiatric treatment programs

This article identifies patients' rights demands and discusses the therapeutic community's potential to act as the conceptual framework for implementing these demands. The author cites five areas in which policy and procedural changes will have to be made: philosophy, physical enviroment, organizational structure, program, and staff roles and attitudes. Recommendations for change are made in each area. The author concludes that the therapeutic community concept and its philosophy of treatment provide a viable alternative to traditional mental health policy and practice and have the capacity to become the conceptual framework for future residential treatment.     

Initial response to drugs in depressive illness and psychiatric and community adjustment a year later.

Three hundred and sixty depressed in-patients initially treated with imipramine, chlorpromazine or a placebo were re-evaluated a year later. Patients showing the poorest adjustment at one year were those who failed to show a good initial response to treatment and those who responded positively to a placebo.     

Halfway house and family involvement as related to community adjustment for ex-residents of a psychiatric halfway house.

What variables are highly correlated with successful community adjustment? A group of ex-patients who left a halfway house to return to the community were interviewed around their active involvement and perceived support from the staff members of the halfway house, while living on their own or with their families. There was a highly positive relationship between continuing contact with the halfway house and the level of adjustment in the community. The implications for understanding the nature, continuity, and purpose of social supports for this group are discussed.     

Psychological community integration among people with psychiatric disabilities and nondisabled community members

This study examined individual and neighborhood predictors of the psychological community integration of people with psychiatric disabilities and nondisabled community members. One hundred twenty‐three adults (60 psychiatrically disabled, 63 general community residents), completed measures of sense of community, life satisfaction, psychiatric symptoms, and perceptions of neighborhood. Mental health consumers living in independent scatter‐site apartments did not differ from other community members in either sense of community or life satisfaction. Among mental health consumers, neither symptoms nor demographic variables predicted sense of community, whereas objective neighborhood characteristics did. Conversely, among community members, age and symptoms predicted sense of community while objective neighborhood characteristics did not; perceived neighborhood characteristics predicted sense of community in both samples. Findings suggest that consumers living in independent housing may achieve levels of psychological community integration comparable to other community members, and that neighborhood factors impact degree of community integration in this population. © 2011 Wiley Periodicals, Inc.     

Treatment of psychiatric symptoms associated with neurosyphilis

There is currently no consensus on how to manage the psychiatric manifestations of neurosyphilis, despite the resurgence of this condition. The authors present five cases of neurosyphilis in inpatient psychiatric settings that manifested with predominantly psychiatric symptoms and were appropriately diagnosed and successfully treated with psychotropic medication concurrent with antibiotic therapy. A review of available data reveals that presently there are no specific guidelines to address psychiatric symptomatology in neurosyphilis. The authors see merit in the prudent use of psychotropic medication to achieve symptom stabilization.     

Psychological and social factors that correlate with dyspnea in heart failure

Dyspnea is a common symptom of heart failure frequently relied upon to assess clinical functioning. The purpose of this study is to explore a broad range of medical, psychological, and social factors that correlate with dyspnea in heart failure patients. Seventy-six participants ranged from well-compensated, ambulatory subjects to those with recent hospitalization for acutely decompensated heart failure. The sample was predominantly male, mean age of 63.5 years, with mild depressive symptoms in 25%. Correlation analysis revealed that dyspnea significantly correlated with depression, fatigue, and overall health perception. Standard regression analyses indicated that depression, fatigue, and overall health perception uniquely contributed to dyspnea, explaining 38.0% of the total variance. The present study confirms that dyspnea is multifactorial, with links to psychological distress and overall health perception.     

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

Somatic missense mutations can initiate tumorogenesis and, conversely, anti-tumor cytotoxic T cell (CTL) responses. Tumor genome analysis has revealed extreme heterogeneity among tumor missense mutation profiles, but their relevance to tumor immunology and patient outcomes has awaited comprehensive evaluation. Here, for 515 patients from six tumor sites, we used RNA-seq data from The Cancer Genome Atlas to identify mutations that are predicted to be immunogenic in that they yielded mutational epitopes presented by the MHC proteins encoded by each patient’s autologous HLA-A alleles. Mutational epitopes were associated with increased patient survival. Moreover, the corresponding tumors had higher CTL content, inferred from CD8A gene expression, and elevated expression of the CTL exhaustion markers PDCD1 and CTLA4. Mutational epitopes were very scarce in tumors without evidence of CTL infiltration. These findings suggest that the abundance of predicted immunogenic mutations may be useful for identifying patients likely to benefit from checkpoint blockade and related immunotherapies.The accumulation of somatic mutations underlies the initiation and progression of most cancers by conferring upon tumor cells unrestricted proliferative capacity (Hanahan and Weinberg 2011). The analysis of cancer genomes has revealed that tumor mutational landscapes (Vogelstein et al. 2013) are extremely variable among patients, among different tumors from the same patient, and even among the different regions of a single tumor (Gerlinger et al. 2012). There is a need for personalized strategies for cancer therapy that are compatible with mutational heterogeneity, and in this regard, immune interventions that aim to initiate or enhance anti-tumor immune responses hold much promise. Therapeutic antibodies and chimeric antigen receptor (CAR) technologies have shown anti-cancer efficacy (Fox et al. 2011), but such antibody-based approaches are limited to cell surface target antigens (Slamon et al. 2001; Coiffier et al. 2002; Yang et al. 2003; Cunningham et al. 2004; Kalos et al. 2011). In contrast, most tumor mutations are point mutations in genes encoding intracellular proteins. Short peptide fragments of these proteins, after intracellular processing and presentation at the cell surface as MHC ligands, can elicit T cell immunoreactivity. Further, the presence of tumor infiltrating lymphocytes (TIL), in particular, CD8⁺ T cells, has been associated with increased survival (Sato et al. 2005; Nelson 2008; Oble et al. 2009; Yamada et al. 2010; Gooden et al. 2011; Hwang et al. 2012), suggesting that the adaptive immune system can mount protective anti-tumor responses in many cancer patients (Kim et al. 2007; Fox et al. 2011). The antigen specificities of tumor-infiltrating T cells remain almost completely undefined (Andersen et al. 2012), but there are numerous examples of cytotoxic T cells recognizing single amino acid coding changes originating from somatic tumor mutations (Lennerz et al. 2005; Matsushita et al. 2012; Heemskerk et al. 2013; Lu et al. 2013; Robbins et al. 2013; van Rooij et al. 2013; Wick et al. 2014). Thus, the notion that tumor mutations are reservoirs of exploitable neo-antigens remains compelling (Heemskerk et al. 2013). For a mutation to be recognized by CD8⁺ T cells, the mutant peptide must be presented by MHC I molecules on the surface of the tumor cell. The ability of a peptide to bind a given MHC I molecule with sufficient affinity for the peptide-MHC complex to be stabilized at the cell surface is the single most limiting step in antigen presentation and T cell activation (Yewdell and Bennink 1999). Recently, several algorithms have been developed that can predict which peptides will bind to given MHC molecules (Nielsen et al. 2003; Bui et al. 2005; Peters and Sette 2005; Vita et al. 2010; Lundegaard et al. 2011), thereby providing guidance into which mutations are immunogenic.The Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov/) is an initiative of the National Institutes of Health that has created a comprehensive catalog of somatic tumor mutations identified using deep sequencing. As a member of The Cancer Genome Atlas Research Network, our center has generated extensive tumor RNA-seq data. Here, we have used public TCGA RNA-seq data to explore the T cell immunoreactivity of somatic missense mutations across six tumor sites. This type of analysis is challenged not only by large numbers of mutations unique to individual patients, but also by the complexity of personalized antigen presentation by MHC arising from the extreme HLA allelic diversity in the outbred human population. Previous studies have explored the potential immunogenicity of tumor mutations (Segal et al. 2008; Warren and Holt 2010; Khalili et al. 2012), but these have been hampered by small sample size and the inability to specify autologous HLA restriction. Recently, we described a method of HLA calling from RNA-seq data that shows high sensitivity and specificity (Warren et al. 2012). Here, we have obtained matched tumor mutational profiles and HLA-A genotypes from TCGA subjects and used these data to predict patient-specific mutational epitope profiles. The evaluation of these data together with RNA-seq-derived markers of T cell infiltration and overall patient survival provides the first comprehensive view of the landscape of potentially immunogenic mutations in solid tumors.     

Histologic characteristics of non-microsatellite-instable colon adenomas correlate with distinct molecular patterns

Colon carcinogenesis encompasses the stepwise accumulation of genomic aberrations correlated with the transition of aberrant crypt-adenoma-carcinoma. Recent data have revealed that, in addition to the microsatellite-instable phenotype, the chromosome instability pathway, representing four fifth of the colon carcinoma, could be involved in heterogeneous molecular alterations. Our project was aimed at determining the existence of distinct molecular subtypes in 159 non-microsatellite-instable colon polyps and their correlation with histology and dysplasia, using allelotyping, MGMT promoter gene methylation status, and K-RAS mutation analyses. Allelic imbalance, MGMT methylation, and K-RAS mutations arise in 62%, 39%, and 32% of polyps, respectively. Only 14% of polyps had no alterations. A 2-way hierarchical clustering analysis of the allelic imbalances identified subgroups of polyps according to their allelic imbalance frequency and distribution. Not only tubulovillous adenoma but also high-grade adenomas were correlated with high global allelic imbalance frequency (P = .005 and P = .003), with allelic imbalance at microsatellites targeting chromosomes 1, 6, and 9. In conclusion, the data presented in this study show that a large heterogeneity exists in the molecular patterns of alterations in precancerous colon lesions, favoring different modes of tumor initiation. Therefore, molecular alterations correlated with tubulovillous-type and high-grade dysplasia could represent targets identifying predictive factors of progression.     

Psychosocial variables that affect the psychological adjustment of ivdu patients with AIDS

The influences of coping strategies and of perceived social support from family and friends on the psychological adjustment of intravenous drug users (IVDUs) with Acquired Immunodeficiency Syndrome (AIDS) were investigated. Twenty-seven male AIDS patients with a history of intravenous drug use completed a demographic questionnaire, Trails-B, the Ways of Coping Questionnaire, Perceived Social Support from Family, Perceived Social Support from Friends, and the Mental Health Inventory. Unexpected results were obtained: The only coping strategy to correlate significantly with psychological adjustment was “Seeking Social Support,” and perceived social support from family correlated positively with psychological adjustment, but perceived social support from friends did not. Interpretations and implications of these findings are presented.     

Sex differences in neurochemical markers that correlate with behavior in aging mice.

Sex differences in neurochemical markers that correlate with behavior in aging mice NEUROBIOL AGING. We examined whether the enzymatic activities of choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) were altered similarly with age in male and female mice, and whether these changes were correlated with age-related alterations in memory and anxiety. ChAT and GAD activities were measured in neocortex, hippocampus, and striatum of behaviorally characterized male and female C57BL/6 mice (5, 17, and 25 months). Generally, ChAT activity was increased, and GAD activity decreased, with age. However, disparate changes were revealed between the sexes; activities of both enzymes were decreased in 17-month males, whereas alterations in females were not observed until 25-months. Furthermore, enzyme-behavior correlations differed between the sexes; in males, ChAT activity was related to one behavioral task, whereas in females, activities of both enzymes were correlated with multiple tasks. Significant enzyme-behavior correlations were most evident at 17 months of age, likely the result of behavioral and enzymatic sex differences at this age. These data represent the first comprehensive report illustrating differential alterations of ChAT and GAD activities in aging male and female mice.